The proposed studies will examine the mechanism by which exogenous cholesterol inhibits the synthesis of cholesterol in the liver and the various other tissues of higher animals. They will also attempt to elucidate the mechanism of the deletion of this feedback system in all known malignant cells. The detailed mechanism of the humoral feedback control of cholesterol synthesis has been shown in this laboratory to involve specifically the production of mevalonic acid. The enzyme responsible for mevalonic acid synthesis; beta-hydroxy-beta- methylglutaryl Coenzyme A reductase (HMG CoA), has been purified and its properties in the normal and various pathologic states will be determined. Similarly, the significance of the cholesterol feedback system in various non-hepatic tissues will be examined. The significance of the loss of feedback control of HMG CoA reductase in malignant cells will be examined by determining whether the production of this enzyme is deranged in malignant tissues. An extensive effort will likewise be made to relate loss of feedback control to the malignant and premalignant state, with specific attempts being made to relate these defects to alterations in the cell membrane, and hence, to the loss of contact inhibition, which is known to characterize the malignant cell.